title: Regulation of fear responses by striatal and extrastriatal adenosine A2A receptors in forebrain.
abstract: BACKGROUND
  Adenosine A2A receptors (A2ARs) are enriched in the striatum but are also present at lower levels in the extrastriatal forebrain (i.e., hippocampus, cortex), integrating dopamine, glutamate, and brain-derived neurotrophic factor (BDNF) signaling, and are thus essential for striatal neuroplasticity and fear and anxiety behavior.
  
  
  METHODS
  We tested two brain region-specific A2AR knockout lines with A2ARs selectively deleted either in the striatum (st-A2AR KO) or the entire forebrain (striatum, hippocampus, and cortex [fb-A2AR KO]) on fear and anxiety-related responses. We also examined the effect of hippocampus-specific A2AR deletion by local injection of adeno-associated virus type 5 (AAV5)-Cre into floxed-A2AR knockout mice.
  
  
  RESULTS
  Selectively deleting A2ARs in the striatum increased Pavlovian fear conditioning (both context and tone) in st-A2AR KO mice, but extending the deletion to the rest of the forebrain apparently spared context fear conditioning and attenuated tone fear conditioning in fb-A2AR KO mice. Moreover, focal deletion of hippocampal A2ARs by AAV5-Cre injection selectively attenuated context (but not tone) fear conditioning. Deletion of A2ARs in the entire forebrain in fb-A2AR KO mice also produced an anxiolytic phenotype in both the elevated plus maze and open field tests, and increased the startle response. These extrastriatal forebrain A2AR behavioral effects were associated with reduced BDNF levels in the fb-A2AR KO hippocampus.
  
  
  CONCLUSIONS
  This study provides evidence that inactivation of striatal A2ARs facilitates Pavlovian fear conditioning, while inactivation of extrastriatal A2ARs in the forebrain inhibits fear conditioning and also affects anxiety-related behavior.
authors.affiliation: Molecular Neuropharmacology Laboratory, Department of Neurology, and Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Wei
authors.affiliation: Molecular Neuropharmacology Laboratory, Department of Neurology, and Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts; Center for Neuroscience and Cell Biology, CNC-University of Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Elisabete
authors.initials: E
authors.lastname: Augusto
authors.affiliation: Center for Neuroscience and Cell Biology, CNC-University of Coimbra, Coimbra, Portugal.
authors.forename: Catarina A
authors.initials: CA
authors.lastname: Gomes
authors.affiliation: R.S. Dow Neurobiology Laboratories, Legacy Research Institute, Portland, Oregon; Laboratory of Behavioural Neurobiology, Swiss Federal Institute of Technology Zurich, Schwerzenbach, Switzerland.
authors.forename: Philipp
authors.initials: P
authors.lastname: Singer
authors.affiliation: Molecular Neuropharmacology Laboratory, Department of Neurology, and Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: R.S. Dow Neurobiology Laboratories, Legacy Research Institute, Portland, Oregon.
authors.forename: Detlev
authors.initials: D
authors.lastname: Boison
authors.affiliation: Center for Neuroscience and Cell Biology, CNC-University of Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Cunha
authors.affiliation: R.S. Dow Neurobiology Laboratories, Legacy Research Institute, Portland, Oregon; Laboratory of Behavioural Neurobiology, Swiss Federal Institute of Technology Zurich, Schwerzenbach, Switzerland.
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Yee
authors.affiliation: Molecular Neuropharmacology Laboratory, Department of Neurology, and Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts. Electronic address: chenjf@bu.edu.
authors.forename: Jiang-Fan
authors.initials: JF
authors.lastname: Chen
mesh_terms: D000818:Animals; D001007:Anxiety / Q000378:metabolism; D003214:Conditioning, Classical; D003342:Corpus Striatum / Q000378:metabolism*; D005239:Fear / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016548:Prosencephalon / Q000378:metabolism*; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism*; D013216:Reflex, Startle
chemical_list: D043705:Receptor, Adenosine A2A
keywords: Adenosine A(2A) receptor; BDNF; anxiety; cortex; fear conditioning; hippocampus; startle response; striatum